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Purpose To 1) evaluate the clinical efficacy of arthroscopic posterior capsular release for improving range of motion (ROM) in cases of recalcitrant flexion contracture and 2) determine patient‐reported outcomes (PROs) postoperatively. Methods Retrospective chart review was performed to identify patients who underwent arthroscopic posterior capsular release due to persistent extension deficit of the knee despite comprehensive nonoperative physical therapy between 2008 and 2021. Knee ROM and PROs (International Knee Documentation Committee [IKDC], Tegner, and visual analog scale [VAS]) were collected at final follow‐up. Results Overall, 22 patients were included with a median age of 37 years (interquartile range [IQR]: 20.5‐44.3). Of these, 8 (36%) were male and 14 (64%) were female, and average follow‐up was 3.7 ± 3.3 years. The most common etiology was knee flexion contracture after anterior cruciate ligament (ACL) reconstruction (59%). All patients failed a minimum of 3 months of nonoperative management. Prior to operative intervention, 100% of patients received physical therapy, 64% received extension knee bracing or casting, and 36% received corticosteroid injection. Median preoperative extension was 15° (IQR: 10‐25) compared to 2° (IQR: 0‐5) postoperatively ( P < .001). At final follow‐up, median extension was 0° (IQR: 0‐3.5). Postoperative VAS pain scores at rest (2 vs 0; P = .001) and with use (5 vs 1.8; P = .017) improved at final contact, and most (94%) patients reported maintaining their extension ROM. Patients with ACL‐related extension deficit reported better IKDC (81 vs 51.3; P = .008), Tegner (5.8 vs 3.6; P = .007), and VAS pain scores (rest: 0.2 vs 1.8; P = .008; use: 1.3 vs 5; P = .004) compared to other etiologies. Conclusion Arthroscopic posterior capsular release for recalcitrant flexion contracture provides an effective means for reducing pain and restoring terminal extension. The improvement in extension postoperatively was maintained for most (94%) patients at final follow‐up with a 14% reoperation rate.

8038 Background: Multiple myeloma (MM) predominantly affects older patients (pts) (median age at diagnosis 69 yrs) in whom comorbidities must be considered to manage the disease appropriately. Some anti-MM therapies can be associated with ocular toxicities and require careful attention when used among pts with pre-existing ocular comorbidities (OC). In 2018, 41% of Medicare enrollees had OC. Despite the potential implication on treatment decisions, information on pre-existing OC (e.g., disorders of lens, glaucoma) in MM pts is limited. This study aims to describe the prevalence of OCs among real-world pts with MM in 2011-2020 in the US. Methods: Adults with newly diagnosed MM (NDMM) with or without treatment, with 1L systemic therapy, and with relapsed/refractory MM (RRMM) who received up to 4 lines of systemic therapies (LOT) for MM were identified in the IQVIA PharMetrics Plus data. The index date was the date of initial MM diagnosis or a LOT initiation date. The prevalence of OC in each group was defined as the presence of any OC ICD 9/10 diagnosis codes in the 12 months prior to the index date. OCs (e.g., disorders of conjunctiva, lens, choroid, retina, glaucoma) were considered a potentially MM-related disease manifestation or MM treatment-related toxicity based on published literature and clinical expert opinion. Results: The median age at initial MM diagnosis was 64 yrs overall (N=49,814), and 63 yrs among treated pts (N=22,963). The median age was 63 yrs at 1L initiation and 64 yrs at 2L, 3L, and 4L initiation. The prevalence of OC at initial MM diagnosis was 39.0% overall and 35.2% among treated pts (Table). The OC prevalence was 35.8% prior to 1L initiation and higher in RRMM pts (42.1%, 44.9%, and 45.7% prior to 2L, 3L, and 4L initiation, respectively). This trend was observed across all OC categories, among MM-related OCs, and across all age groups. The prevalence of OC by MM stage was stable over the years. Conclusions: Approximately 40% of NDMM pts have a pre-existing OC, and the prevalence increases with the number of LOT in RRMM. While some OC may be due to aging, the impact of OC on treatment decisions for MM should be explored. [Table: see text]

5025 Background: Prospective reports suggest metastasis directed therapy (MDT) in oligometastatic castration sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. Here we present long term outcomes of the phase II STOMP and ORIOLE trials and assess the ability of a high-risk (HiRi) mutational signature to provide prognostic and predictive information regarding MDT response. Methods: Patients with omCSPC (< 3 lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54) randomized to MDT or observation were pooled. The primary endpoint was progression-free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. Secondary endpoint was radiographic PFS (rPFS) defined as radiographic progression or death. Both were calculated using the Kaplan-Meier method and stratified by treatment group. Next generation sequencing (NGS) was performed to identify a HiRi mutational signature defined as pathogenic mutations within ATM, BRCA1/2, Rb1, or TP53. Cox proportional hazards regressions were fit to calculate hazard ratios (HR) and assess the prognostic and predictive values of HiRi mutational status. Results: Median follow-up was 52.5 months. Median PFS was prolonged with MDT (11.9 months) compared to observation (5.9 months) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001). MDT was associated with PSA decrease in a majority of patients (84%) as compared to the observation group (41%). On NGS, the incidence of a pathogenic mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for PFS -- in those without a HiRi mutation median PFS was 11.9 months compared to 5.9 months in those with a HiRi mutation (HR of 1.74, p = 0.06). HiRi mutation was also prognostic for rPFS -- those without a high-risk mutation experienced median rPFS of 22.6 months compared to 10.0 months in those with a high-risk mutation (HR 2.62, p < 0.01). Tumors without a HiRi mutation treated with MDT experienced the longest PFS (13.4 months) while those with a HiRi randomized to observation experienced the shortest PFS (2.8 months). Stratifying by both treatment arms and HiRi status appeared to show a differential benefit to MDT, with those with HiRi mutations experiencing a larger relative magnitude of benefit to treatment: (HiRi mutation: HR of 0.05, p < 0.01; no HiRi mutation: HR of 0.42, p = 0.01; p interaction, 0.12) suggesting a HiRi mutational status can provide information regarding differential response to treatment. Conclusions: Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained benefit to MDT over observation. A HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT. Future studies are needed to optimize patient selection. Clinical trial information: NCT02680587.

5011 Background: Emerging data suggest metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET/CT) can detect occult metastatic disease and has been proposed as a biomarker for treatment response. Herein we identify and validate a PSMA-PET biomarker for clinical outcomes following MDT in omCSPC. Methods: This was an international multi-institutional retrospective study of two completely independent cohorts of men with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation therapy (SABR) who underwent PSMA-PET/CT prior to and 3-6 months after treatment. Pre- and post-SABR PSMA-PET/CT standardized uptake value (SUV) was measured for all lesions and PSMA response defined discretely using a cutpoint of ≥ 30% decrease in SUVmax. PSMA-PET response was correlated with lesion local control (LLC), radiographic progression-free survival (rPFS) defined using conventional and PET imaging, and metastasis-free survival (MFS) defined by conventional imaging alone. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with median follow-up of 29 months (IQR 18.5-41.3). Following SABR, 78.4% of lesions experienced a partial or complete PSMA response. Multivariable analysis demonstrated SUV response significantly associated with improved LLC (HR = 9.97, 95%CI 3.92-25.4; p < 0.01). Patients with PSMA response in all lesions experienced significantly better rPFS (HR = 0.49, 95%CI 0.26-0.92; p = 0.03) compared to their counterparts and this maintained significance within both the discovery (p < 0.01) and validation (p = 0.01) cohorts. Within the discovery cohort, patients with PSMA response in all lesions also experienced significantly improved MFS (HR = 0.24, 95%CI 0.07-0.85; p = 0.03); analysis of the independent validation cohort is ongoing. Conclusions: Following SABR, PSMA-PET response is a robust and externally validated radiographic biomarker for rPFS and appears to be associated with MFS pending validation. This approach holds promise for guiding clinical management of omCSPC.

4055 Background: Tumor microenvironmental (TME) features including tumor stroma ratio (TSR), tumor infiltrating lymphocytes (TILs) and tumor budding (TB), may be associated with tumor metastatic potential. We sought to identify the association of these features with prognosis of patients with resectable intestinal-type gastric cancer. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 493 patients (stage I, n=225; stage II, n=119; stage III, n=149) at two university hospitals between 2010 and 2016. Cutpoints were as follows: TSR (50%), TILs (median), and TB (Bd0-Bd3). TME features and their association with clinicopathological characteristics, time-to-recurrence (TTR) and overall survival (OS) were analyzed by univariate and multivariate Cox methods.. Results: Among 493 patients, high TSR, low TILs and high TB (Bd1-Bd3) were significantly associated with higher histological grade, larger tumor size, and increased T and N stages. Each of these features was significantly associated with poorer TTR and OS at 5 years. In Cox multivariable analysis, N stage and TSR were the only variables that were significantly associated with TTR and OS (Table). The relative contribution (%) of TSR to TTR ranked second (17.5%) behind N stage (49.2%) and ahead of TILs (7.2%) and TB (0.1%). Conclusions: Among TME features, TSR was the most robust and was significantly and independently associated with TTR and OS. The relative contribution of TSR to TTR was second only to nodal status. [Table: see text]

Abstract Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL–not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881–R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.

Higher levels of tumor-derived extracellular vesicles are detected in metastatic prostate cancer compared to localized prostate cancer by standardized and calibrated flow cytometry.

Background: Wrestling is a physically demanding sport, with young athletes prone to anterior cruciate ligament (ACL) injuries. There is a paucity of data evaluating the results of ACL reconstruction (ACLR) in this cohort. Purpose: To assess return to sport (RTS), patient-reported outcomes, reoperation rates, and graft survival after ACLR in a large cohort of competitive wrestlers at midterm follow-up. Study Design: Case series; Level of evidence, 4. Methods: We identified all competitive wrestlers (club, high school, collegiate, or professional) with a history of an ACLR at a single institution between 2000 and 2019. Graft failure was defined as a retear (as determined via clinical or advanced imaging evaluation) and/or revision ACLR. All patients were contacted for determination of reinjury rates; current sport status; and pain visual analog scale, International Knee Documentation Committee, and Tegner activity scores. Results: Included were 107 knees in 103 wrestlers, with a median follow-up time of 5.9 years (interquartile range [IQR], 3.9-10.3 years). The median age was 17 years (IQR, 15-18 years), with 106 (99%) male patients, and the distribution of bone–patellar tendon–bone (BTB) and hamstring tendon (HT) autografts was 64 (60%) and 43 (40%), respectively. At final follow-up, 80% of athletes were able to RTP at a median of 280 days (IQR, 212-381 days). Graft failure occurred in 14 (13%) knees at a median time of 1.8 years (IQR, 0.7-5.3 years) after the index ACLR. BTB autograft demonstrated a lower failure rate compared with HT autograft (8% vs 21%; P = .044) and was associated with better survival compared with HT autograft up to 15 years after the index ACLR (90.4% vs 76.3%; P = .030). When compared by graft diameter, HT autografts of at least 7.5 mm were not associated with a lower graft failure than BTB constructs of all sizes ( P = .205). Conclusion: Return to competitive wrestling was observed in 80% of athletes after ACLR, with 14% of wrestlers experiencing graft failure. BTB autograft was associated with better survival than HT autograft.